Hot off the presses! Aug 11 Neuron

The Aug 11 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Semaphorin Breaks Symmetry
  - Neuron 71(3):381-382 (2011)
  Axon-dendrite polarity is likely instructed by extrinsic cues in the developing nervous system, though the mechanisms governing this process remain to be fully elucidated. In this issue of Neuron, Shelly et al. show that the axon guidance cue Semaphorin 3A can promote dendrite growth by inhibiting axon specification.
• Tracking Down the Molecular Substrates of Stress: New Roles for p38α MAPK and Kappa-Opioid Receptors
  - Neuron 71(3):383-385 (2011)
  In this issue, Bruchas et al. (2011) uncover a novel stress-induced p38α MAPK signaling cascade within serotonergic neurons of the dorsal raphe nucleus that mediates depressive and drug-seeking behaviors. Their findings have potentially important implications for medication development.
• The Battle over Inhibitory Synaptic Plasticity in Satiety Brain Circuits
  - Neuron 71(3):385-387 (2011)
  The synaptic basis underlying food intake is poorly understood. New research shows that an animal's satiety state dictates the polarity of long-term inhibitory synaptic plasticity in the hypothalamus, which is mediated by an activity-dependent competition between endocannabinoid and nitric oxide signaling.
• New Insights into Motor Cortex
  - Neuron 71(3):387-388 (2011)
  An exciting new experiment on the motor cortex of monkeys, by Shenoy and colleagues, begins to elucidate how the neuronal ensemble travels in a systematic fashion through state space. This trajectory through state space may help to explain how the motor cortex sets up and then triggers arm movements.
• Regulated Reprogramming in the Regeneration of Sensory Receptor Cells
  - Neuron 71(3):389-405 (2011)
  Vision, olfaction, hearing, and balance are mediated by receptors that reside in specialized sensory epithelial organs. Age-related degeneration of the photoreceptors in the retina and the hair cells in the cochlea, caused by macular degeneration and sensorineural hearing loss, respectively, affect a growing number of individuals. Although sensory receptor cells in the mammalian retina and inner ear show only limited or no regeneration, in many nonmammalian vertebrates, these sensory epithelia show remarkable regenerative potential. We summarize the current state of knowledge of regeneration in the specialized sense organs in both nonmammalian vertebrates and mammals and discuss possible areas where new advances in regenerative medicine might provide approaches to successfully stimulate sensory receptor cell regeneration. The field of regenerative medicine is still in its infancy, but new approaches using stem cells and reprogramming suggest ways in which the potential! for regeneration may be restored in individuals suffering from sensory loss.
• The Neurovascular Link in Health and Disease: Molecular Mechanisms and Therapeutic Implications
  - Neuron 71(3):406-424 (2011)
  At first sight, the nervous and vascular systems seem to share little in common. However, neural and vascular cells not only are anatomically closely tied to each other, but they also utilize and respond to similar classes of signals to establish correct connectivity and wiring of their networks. Recent studies further provide evidence that this neurovascular crosstalk is more important for understanding the molecular basis of neurological disease than originally anticipated. Moreover, neurovascular strategies offer novel therapeutic opportunities for neurodegenerative disorders.
• Development of Direction Selectivity in Mouse Cortical Neurons
  - Neuron 71(3):425-432 (2011)
  Previous studies of the ferret visual cortex indicate that the development of direction selectivity requires visual experience. Here, we used two-photon calcium imaging to study the development of direction selectivity in layer 2/3 neurons of the mouse visual cortex in vivo. Surprisingly, just after eye opening nearly all orientation-selective neurons were also direction selective. During later development, the number of neurons responding to drifting gratings increased in parallel with the fraction of neurons that were orientation, but not direction, selective. Our experiments demonstrate that direction selectivity develops normally in dark-reared mice, indicating that the early development of direction selectivity is independent of visual experience. Furthermore, remarkable functional similarities exist between the development of direction selectivity in cortical neurons and the previously reported development of direction selectivity in the mouse retina. Together, t! hese findings provide strong evidence that the development of orientation and direction selectivity in the mouse brain is distinctly different from that in ferrets.
• Semaphorin3A Regulates Neuronal Polarization by Suppressing Axon Formation and Promoting Dendrite Growth
  - Neuron 71(3):433-446 (2011)
  Semaphorin 3A (Sema3A) is a secreted factor known to guide axon/dendrite growth and neuronal migration. We found that it also acts as a polarizing factor for axon/dendrite development in cultured hippocampal neurons. Exposure of the undifferentiated neurite to localized Sema3A suppressed its differentiation into axon and promoted dendrite formation, resulting in axon formation away from the Sema3A source, and bath application of Sema3A to polarized neurons promoted dendrite growth but suppressed axon growth. Fluorescence resonance energy transfer (FRET) imaging showed that Sema3A elevated the cGMP but reduced cAMP and protein kinase A (PKA) activity, and its axon suppression is attributed to the downregulation of PKA-dependent phosphorylation of axon determinants LKB1 and GSK-3β. Downregulating Sema3A signaling in rat embryonic cortical progenitors via in utero electroporation of siRNAs against the Sema3A receptor neuropilin-1 also resulted in polarization defects in ! vivo. Thus, Sema3A regulates the earliest step of neuronal morphogenesis by polarizing axon/dendrite formation.
• Rich Regulates Target Specificity of Photoreceptor Cells and N-Cadherin Trafficking in the Drosophila Visual System via Rab6
  - Neuron 71(3):447-459 (2011)
  Neurons establish specific synaptic connections with their targets, a process that is highly regulated. Numerous cell adhesion molecules have been implicated in target recognition, but how these proteins are precisely trafficked and targeted is poorly understood. To identify components that affect synaptic specificity, we carried out a forward genetic screen in the Drosophila eye. We identified a gene, named ric1 homologue (rich), whose loss leads to synaptic specificity defects. Loss of rich leads to reduction of N-Cadherin in the photoreceptor cell synapses but not of other proteins implicated in target recognition, including Sec15, DLAR, Jelly belly, and PTP69D. The Rich protein binds to Rab6, and Rab6 mutants display very similar phenotypes as the rich mutants. The active form of Rab6 strongly suppresses the rich synaptic specificity defect, indicating that Rab6 is regulated by Rich. We propose that Rich activates Rab6 to regulate N-Cadherin trafficking and affects! synaptic specificity.
• Class 5 Transmembrane Semaphorins Control Selective Mammalian Retinal Lamination and Function
  - Neuron 71(3):460-473 (2011)
  In the vertebrate retina, neurites from distinct neuronal cell types are constrained within the plexiform layers, allowing for establishment of retinal lamination. However, the mechanisms by which retinal neurites are segregated within the inner or outer plexiform layers are not known. We find that the transmembrane semaphorins Sema5A and Sema5B constrain neurites from multiple retinal neuron subtypes within the inner plexiform layer (IPL). In Sema5A−/−; Sema5B−/− mice, retinal ganglion cells (RGCs) and amacrine and bipolar cells exhibit severe defects leading to neurite mistargeting into the outer portions of the retina. These targeting abnormalities are more prominent in the outer (OFF) layers of the IPL and result in functional defects in select RGC response properties. Sema5A and Sema5B inhibit retinal neurite outgrowth through PlexinA1 and PlexinA3 receptors both in vitro and in vivo. These findings define a set of ligands and receptors required for the es! tablishment of inner retinal lamination and function.
• v-SNARE Composition Distinguishes Synaptic Vesicle Pools
  - Neuron 71(3):474-487 (2011)
  Synaptic vesicles belong to two distinct pools, a recycling pool responsible for the evoked release of neurotransmitter and a resting pool unresponsive to stimulation. The uniform appearance of synaptic vesicles has suggested that differences in location or cytoskeletal association account for these differences in function. We now find that the v-SNARE tetanus toxin-insensitive vesicle-associated membrane protein (VAMP7) differs from other synaptic vesicle proteins in its distribution to the two pools, providing evidence that they differ in molecular composition. We also find that both resting and recycling pools undergo spontaneous release, and when activated by deletion of the longin domain, VAMP7 influences the properties of release. Further, the endocytosis that follows evoked and spontaneous release differs in mechanism, and specific sequences confer targeting to the different vesicle pools. The results suggest that different endocytic mechanisms generate synaptic! vesicles with different proteins that can endow the vesicles with distinct properties.
• Serotonin 2C Receptor Activates a Distinct Population of Arcuate Pro-opiomelanocortin Neurons via TRPC Channels
  - Neuron 71(3):488-497 (2011)
  Serotonin 2C receptors (5-HT2CRs) expressed by pro-opiomelanocortin (POMC) neurons of hypothalamic arcuate nucleus regulate food intake, energy homeostasis and glucose metabolism. However, the cellular mechanisms underlying the effects of 5-HT to regulate POMC neuronal activity via 5-HT2CRs have not yet been identified. In the present study, we found the putative transient receptor potential C (TRPC) channels mediate the activation of a subpopulation of POMC neurons by mCPP (a 5-HT2CR agonist). Interestingly, mCPP-activated POMC neurons were found to be a distinct population from those activated by leptin. Together, our data suggest that 5-HT2CR and leptin receptors are expressed by distinct subpopulations of arcuate POMC neurons and that both 5-HT and leptin exert their actions in POMC neurons via TRPC channels. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (9907 K)
• Selective p38α MAPK Deletion in Serotonergic Neurons Produces Stress Resilience in Models of Depression and Addiction
  - Neuron 71(3):498-511 (2011)
  Maladaptive responses to stress adversely affect human behavior, yet the signaling mechanisms underlying stress-responsive behaviors remain poorly understood. Using a conditional gene knockout approach, the α isoform of p38 mitogen-activated protein kinase (MAPK) was selectively inactivated by AAV1-Cre-recombinase infection in specific brain regions or by promoter-driven excision of p38α MAPK in serotonergic neurons (by Slc6a4-Cre or ePet1-Cre) or astrocytes (by Gfap-CreERT2). Social defeat stress produced social avoidance (a model of depression-like behaviors) and reinstatement of cocaine preference (a measure of addiction risk) in wild-type mice, but not in mice having p38α MAPK selectively deleted in serotonin-producing neurons of the dorsal raphe nucleus. Stress-induced activation of p38α MAPK translocated the serotonin transporter to the plasma membrane and increased the rate of transmitter uptake at serotonergic nerve terminals. These findings suggest that st! ress initiates a cascade of molecular and cellular events in which p38α MAPK induces a hyposerotonergic state underlying depression-like and drug-seeking behaviors.
• Dendritic Integration in Hippocampal Dentate Granule Cells
  - Neuron 71(3):512-528 (2011)
  Hippocampal granule cells are important relay stations that transfer information from the entorhinal cortex into the hippocampus proper. This process is critically determined by the integrative properties of granule cell dendrites. However, their small diameter has so far hampered efforts to examine their properties directly. Using a combination of dual somatodendritic patch-clamp recordings and multiphoton glutamate uncaging, we now show that the integrative properties of granule cell dendrites differ substantially from other principal neurons. Due to a very strong dendritic voltage attenuation, the impact of individual synapses on granule cell output is low. At the same time, integration is linearized by voltage-dependent boosting mechanisms, only weakly affected by input synchrony, and independent of input location. These experiments establish that dentate granule cell dendritic properties are optimized for linear integration and strong attenuation of synaptic input! from the entorhinal cortex, which may contribute to the sparse activity of granule cells in vivo.
• Endocannabinoids Gate State-Dependent Plasticity of Synaptic Inhibition in Feeding Circuits
  - Neuron 71(3):529-541 (2011)
  Changes in food availability alter the output of hypothalamic nuclei that underlie energy homeostasis. Here, we asked whether food deprivation impacts the ability of GABA synapses in the dorsomedial hypothalamus (DMH), an important integrator of satiety signals, to undergo activity-dependent changes. GABA synapses in DMH slices from satiated rats exhibit endocannabinoid-mediated long-term depression (LTDGABA) in response to high-frequency stimulation of afferents. When CB1Rs are blocked, however, the same stimulation elicits long-term potentiation (LTPGABA), which manifests presynaptically and requires heterosynaptic recruitment of NMDARs and nitric oxide (NO). Interestingly, NO signaling is required for eCB-mediated LTDGABA. Twenty-four hour food deprivation results in a CORT-mediated loss of CB1R signaling and, consequently, GABA synapses only exhibit LTPGABA. These observations indicate that CB1R signaling promotes LTDGABA and gates LTPGABA. Furthermore, the satiety! state of an animal, through regulation of eCB signaling, determines the polarity of activity-dependent plasticity at GABA synapses in the DMH.
• Broad Inhibition Sharpens Orientation Selectivity by Expanding Input Dynamic Range in Mouse Simple Cells
  - Neuron 71(3):542-554 (2011)
  Orientation selectivity (OS) is an emergent property in the primary visual cortex (V1). How OS arises from synaptic circuits remains unsolved. Here, in vivo whole-cell recordings in the mouse V1 revealed that simple cells received broadly tuned excitation and even more broadly tuned inhibition. Excitation and inhibition shared a similar orientation preference and temporally overlapped substantially. Neuron modeling and dynamic-clamp recording further revealed that excitatory inputs alone would result in membrane potential responses with significantly attenuated selectivity, due to a saturating input-output function of the membrane filtering. Inhibition ameliorated the attenuation of excitatory selectivity by expanding the input dynamic range and caused additional sharpening of output responses beyond unselectively suppressing responses at all orientations. This "blur-sharpening" effect allows selectivity conveyed by excitatory inputs to be better expressed, which m! ay be a general mechanism underlying the generation of feature-selective responses in the face of strong excitatory inputs that are weakly biased.
• Single-Trial Neural Correlates of Arm Movement Preparation
  - Neuron 71(3):555-564 (2011)
  The process by which neural circuitry in the brain plans and executes movements is not well understood. Until recently, most available data were limited either to single-neuron electrophysiological recordings or to measures of aggregate field or metabolism. Neither approach reveals how individual neurons' activities are coordinated within the population, and thus inferences about how the neural circuit forms a motor plan for an upcoming movement have been indirect. Here we build on recent advances in the measurement and description of population activity to frame and test an "initial condition hypothesis" of arm movement preparation and initiation. This hypothesis leads to a model in which the timing of movements may be predicted on each trial using neurons' moment-by-moment firing rates and rates of change of those rates. Using simultaneous microelectrode array recordings from premotor cortex of monkeys performing delayed-reach movements, we compare such single-tr! ial predictions to those of other theories. We show that our model can explain approximately 4-fold more arm-movement reaction-time variance than the best alternative method. Thus, the initial condition hypothesis elucidates a view of the relationship between single-trial preparatory neural population dynamics and single-trial behavior.